DOI QR코드

DOI QR Code

Evaluation of the Immunohistochemical Staining Pattern of the mTOR Signaling Proteins in Colorectal Cancers and Adenoma Lesions

대장암과 선종 병변에서 mTOR 신호 단백질의 면역조직화학 염색성 평가

  • Kim, Jin Mok (Department of Pathology, Sungkunkwan University Samsung Changwon Hospital) ;
  • Lee, Hyoun Wook (Department of Pathology, Sungkunkwan University Samsung Changwon Hospital)
  • 김진목 (성균관대학교 삼성창원병원 병리과) ;
  • 이현욱 (성균관대학교 삼성창원병원 병리과)
  • Received : 2017.10.20
  • Accepted : 2017.11.10
  • Published : 2017.12.31

Abstract

Changes in the mammalian target of the rapamycin (mTOR) signaling proteins have been observed in many types of cancer. Accordingly, these proteins have recently become an exciting new target for molecular therapeutics. This study examined the expression of an activated mTOR signaling protein in patients with colorectal adenocarcinoma (CRAC) and colorectal adenoma lesion. Immunohistochemical analysis was performed on human CRAC and adenoma for the mTOR signaling components, including mTOR, phosphorylation, and activation of S6 kinase (p70-S6K), S6 ribosomal protein (S6), and eukaryotic initiation factor 4E-binding protein (4EBP1). A total of 100 cases with colorectal adenocarcinoma (CARC; N=40), adenoma with high-grade intraepithelial neoplasms (HIN; N=30), and adenoma with low-grade intraepithelial neoplasms (LIN; N=30) were enrolled in this study. p-mTOR expression was observed in 30 cases of the CRAC tissues (75%), 9 cases of adenoma with HIN (30%), and 2 cases of adenoma with LIN (7%). In addition, p-S6 expression was observed in 22 cases of CRAC tissues (55%), 8 cases of adenoma with HIN (27%), and 3 cases of adenoma with LIN (10%). A significant correlation was observed among the p-mTOR, p-S6 expression, and the adenoma-carcinoma sequence. Interestingly, the p-S6 protein was activated more in early CRAC than in advanced CRAC.

mTOR 신호전달 단백질의 변화는 다양한 종류의 암에서 관찰 되었다. 따라서 이들 단백질은 최근에 암 치료제에 대한 새롭고 흥미로운 표적이 되고 있다. 우리는 대장암과 선종 환자의 mTOR 세포신호의 활성도를 조사하였다. 면역조직화학적 방법으로 대장암과 선종의 세포신호 단백질 성분인 mTOR, p70-S6K, S6, 4EBP1 발현을 분석하였다. 이번 연구는 모두 100개의 예를 악성(Colorectal Adenocarcinoma, CRAC) 40건, 고등급 선종(Adenoma with High grade intraepithelial neoplasms, HIN) 30건, 저등급 선종(Adenoma with Low-grade intraepithelial neoplasms, LIN) 30건으로 분류하여 진행하였다. p-mTOR의 발현률은 LIN 7%, HIN 30%, CRAC 75%였고 p-S6의 발현률 또한 LIN 10%, HIN 27%, CRAC 55%였다. p-mTOR, p-S6의 발현과 선종-선암 연속성은 중요한 상관관계 있다는 것이 발견되었다. 그리고 흥미롭게도 p-S6 발현률은 진행암보다 초기암에서 더 높았다.

Keywords

References

  1. Brown EJ, Albers MW, Shin TB, Ichikawa K, Keith CT, Lane WS, et al. "A mammalian protein targeted by G 1-arresting rapamycin-receptor complex". Nature. 1994;369(6483):756-758. https://doi.org/10.1038/369756a0
  2. Kim, DH, Sarbassov DD, Ali, SM, King JE, Latek RR, Erdjument-Bromage H, et al. mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell. 2002;110(2):163-176. https://doi.org/10.1016/S0092-8674(02)00808-5
  3. Hermsen M, Postma C, Baak J, Weiss M, Rapallo A, Sciutto A, et al. Colorectal adenoma to carcinoma progression follows multiple pathways of chromosomal instability. Gastroenterology. 2002;123(4):1109-1119. https://doi.org/10.1053/gast.2002.36051
  4. Jackman RJ, Mayo CW. The adenoma-carcinoma sequence in cancer of the colon. Surg Gynecol Obstet. 1951;93(3):327-330.
  5. Nagel R, le Sage C, Diosdado B, van der Waal M, Oude Vrielink JAF, Bolijn A, et al. Regulation of the adenomatous polyposis coli gene by the miR-135 family in colorectal cancer. Cancer Res. 2008;68(14):5795-5802. https://doi.org/10.1158/0008-5472.CAN-08-0951
  6. Toll AD, Fabius D, Hyslop T, Pequignot E, DiMarino AJ, Infantolino A, et al. Prognostic significance of high-grade dysplasia in colorectal adenomas. Colorectal Dis. 2011;13(4): 370-373. https://doi.org/10.1111/j.1463-1318.2010.02385.x
  7. Brenner H, Chang-Claude J, Seiler CM, Rickert A, Hoffmeister M. Protection from colorectal cancer after colonoscopy. Ann Intern Med. 2011;154(1):22-30. https://doi.org/10.7326/0003-4819-154-1-201101040-00004
  8. Mamane Y, Petroulakis E, LeBacquer O, Sonenberg N. mTOR, translation initiation and cancer. Oncogene. 2006;25(48): 6416-6422. https://doi.org/10.1038/sj.onc.1209888
  9. Tee AR, Blenis J. mTOR, translational control and human disease. Semin Cell Dev Biol. 2005;16(1):29-37. https://doi.org/10.1016/j.semcdb.2004.11.005
  10. Noh WC, Kim YH, Kim MS, Koh JS, Kim HA, Moon NM, et al. Activation of the mTOR signaling pathway in breast cancer and its correlation with the clinicopathologic variables. Breast Cancer Res Treat. 2008;1109(3):477-483
  11. No JH, Jeon YT, Park IA, Kim YB, Kim JW, Park NH, et al. Activation of mTOR signaling pathway associated with adverse prognostic factors of epithelial ovarian cancer. Gynecol Oncol. 2011;121(1):8-12. https://doi.org/10.1016/j.ygyno.2010.12.364
  12. Faivre S, Kroemer G, Raymond E. "Current development of mTOR inhibitors as anticancer agents". Nat Rev Drug Discov. 2006;5(8):671-88. https://doi.org/10.1038/nrd2062
  13. Fingar DC, Salama S, Tsou C, Harlow E, Blenis J. Mammalian cell size is controlled by mTOR and its downstream targets S6K1 and 4EBP1/eIF4E. Genes Dev. 2002;16(12):1472-1487. https://doi.org/10.1101/gad.995802
  14. Brown EJ, Beal PA, Keith CT, Chen J, Shin, TB, Schreiber, SL. Control of p70 s6 kinase by kinase activity of FRAP in vivo. Nature. 1995;377(6548):441-446. https://doi.org/10.1038/377441a0
  15. Burnett PE, Barrow RK, Cohen NA, Snyder SH, Sabatini DM. RAFT1 phosphorylation of the translational regulators p70 S6 kinase and 4E-BP1. Proc Natl Acad Sci. 1998;95(4):1432-1437 https://doi.org/10.1073/pnas.95.4.1432
  16. Gingras AC, Gygi SP, Raught B, Polakiewicz RD, Abraham RT, Hoekstra, M.F. et al. Regulation of 4E-BP1 phosphorylation: A novel two step mechanism. Genes Dev. 1999;13:1422-1437. https://doi.org/10.1101/gad.13.11.1422
  17. Inoki K, Ouyang H, Li Y, Guan KL. Signaling by target of rapamycin proteins in cell growth control. Micro Mol Biol Rev. 2005;69(1):79-100. https://doi.org/10.1128/MMBR.69.1.79-100.2005
  18. Lazaris-Karatzas A, Montine KS, Sonenberg N. Malignant transformation by a eukaryotic initiation factor subunit that binds to mRNA cap. Nature. 1990;345(6275):544-7. https://doi.org/10.1038/345544a0
  19. Graff JR, Boghaert ER, DeBenedetti A, Tudor DM, Zimmer SG. Reduction of translation initiation factor 4E reduces tumor growth, invasion and metastasis of ras transformed cloned rat embryo fibroblast. Int J Cancer. 1995;60(17):255-63.